Aging is the single most important risk factor for late-onset Alzheimer's disease (AD), which represents ~97% of all cases of AD dementia. We have recently shown that normal aging of the brain is characterized by a progressive switch from the TrkA to the p75NTR receptor system that leads to activation of the second messenger ceramide and increased production of amyloid 2-peptide (A2). These effects can be blocked by genetic disruption of p75NTR and biochemical inhibition of neutral sphingomyelinase (nSMase), the enzyme that activates ceramide. In the Preliminary Studies section we show that activation of IGF1-R signaling up- regulates p75NTR while down-regulating TrkA. The signaling cascade downstream of IGF1-R requires IRS2, PI3K, PIP3, Egr-1, HIPK2, and is under the inhibitory control of PTEN and p44. We also show that IGF1-R acts up-stream of p75NTR/TrkA in the regulation of A2 generation. In addition, hyperactivation of IGF1-R signaling in p44+/+ transgenic mice leads to an accelerated form of aging, early TrkA to p75NTR switch, and increased production of A2. Finally, p44+/+, APP695/swe double-transgenic mice develop an early and severe form of neurodegeneration that results in death by the 3rd month of life. The above events were all linked to overproduction of ceramide and molecular stabilization of BACE1. Therefore, our studies have uncovered a novel molecular link between aging and AD, and are leading the field toward new directions that, if successful, will have direct impact on the prevention of a disease that is projected to affect ~15 million Americans by the year 2050. The long-term objective of this application is to analyze the role of IGF1-R signaling in the pathogenesis of AD and to assess whether it can serve as a novel target for the prevention of late-onset AD. Specific Aim 1 will analyze the role of the signaling molecules that act down-stream of IGF1-R. We have described several biochemical and genetic studies in both primary neurons and neuronal cell lines. The biochemical approach includes in vitro-assays and pharmacologic inhibitors, whereas the genetic approach includes siRNA, antisense oligonucleotides, and dominant mutants of the targeted signaling molecules. We will also use organotypic brain cultures and animal models of aging, including normally-fed (normal aging) and caloric-restricted (delayed aging) wild-type mice, and p44+/+ mice (accelerated aging). Specific Aim 2 will analyze the role of IGF1-R signaling on AD pathology in a our newly developed p44+/+, APP695/swe mouse model. For this purpose, we have described biochemical, histological, and cognitive approaches. In addition, we will also treat p44+/+, APP695/swe mice with manumycin A (which inhibits the production of ceramide) to assess whether we can block/delay the pathology. Finally, the coordination between Aim 1, where we plan to identify biochemical targets, and Aim 2, where we plan to characterize the first AD mouse model that is under the control of a hyperactive aging program, will allow us to test novel pharmacological strategies to prevent the AD-risk associated with aging. PUBLIC HEALTH RELEVANCE: Aging is the single most important risk factor for Alzheimer's disease (AD), which represents the most common cause of dementia in the World. Because of the increase in life expectancy that we are experiencing, AD is predicted to affect 45 million individuals worldwide by the year 2050. During the last three years we have identified a novel molecular pathway that links aging to AD neuropathology. We have also developed the first mouse model that allows to study the effect of aging on AD. Given the role that these events play in the pathogenesis of AD, our results have profound implications for the neurobiology of the disease and for the prevention of the AD-risk associated with aging. The long-term objective of this proposal is to expand upon our findings and fully characterize the molecular pathway that we have identified. This will allow us to design new pharmacologic approaches for the prevention of AD.